Background
The global public health burden of asthma is significant, with an estimated global prevalence of 358 million [
1]. The Disability Adjusted Life Years (DALYs) attributed to asthma globally across all ages was 23.7 million in 2016 [
2]. This chronic condition therefore represents a significant burden to healthcare systems and to individuals living with asthma. While asthma research has received extensive attention worldwide, research on asthma control and the effectiveness of public health interventions is still limited within the Gulf Cooperation Council (GCC) countries (namely Bahrain, Kuwait, Oman, Qatar, Saudi Arabia and the United Arab Emirates [UAE]).
Insight into the prevalence and burden of asthma within the region has been provided by the SNAPSHOT programme [
3], a study of large random samples from the general populations of Middle Eastern countries including Kuwait, Saudi Arabia and the UAE (Gulf cluster). The reported prevalence of asthma was 6.4% across all of the assessed Middle Eastern countries and 7.6% within the Gulf cluster [
3].
The extent to which the effects of asthma can be seen in individual patients, or reduced by pharmacological or non-pharmacological interventions is known as asthma control [
4]. The Epidemiological Study on the Management of Asthma in Asthmatic Middle East Adult Population (ESMAA) re-affirmed the low levels of asthma control in the GCC countries, with the highest levels reported as 41% and 42.6% in Qatar and Kuwait respectively [
5].
Numerous risk and prognostic factors have been associated with asthma control [
6]. These include genetics, tobacco exposure, occupational exposure, air pollution, respiratory infection, and adherence to treatment [
7,
8]. While factors associated with asthma control are generally thought to be similar worldwide, the strength of association may vary both within and, between different populations [
9]. Knowledge of local factors associated with asthma control is therefore critical in implementing effective asthma management strategies. Consequently, findings from studies conducted within specific populations of interest, or generalisable to these populations, are vital in informing asthma management. Despite numerous published studies, there is a paucity of evidence synthesis on asthma control factors in the GCC countries. More significantly, evidence relating to the effectiveness of asthma interventions in clinical practice within GCC countries is sparse. Given that the goal of asthma management is to achieve optimal asthma control, it is imperative to provide asthma treatment guideline developers with timely evidence that is relevant to the local population.
Inhaled corticosteroid (ICS) and long-acting beta-agonist (LABA) fixed dose combinations (FDC) are the most reported therapeutic intervention for asthma management in the GCC countries, with a significant proportion of patients in the GCC region being in steps 3 and 4 of the Global Initiative of Asthma (GINA) management guidelines [
4,
10]. The place of FDC of ICS and LABA in the management of asthma is also recognized in local treatment guidelines within the GCC, such as the Saudi Initiative for Asthma guidelines [
11], the National Asthma Management Guidelines in Oman [
12] and the National Clinical Guidelines on the diagnosis and management of asthma in adults by the Qatar Ministry of Public Health [
13]. A recent study within the region has shown that patients on ICS/LABA FDCs were more likely to achieve asthma control compared to patients not managed on this therapy [
14]. This may provide possible explanation as to why ICS/LABA FDC is the choice of many treating physicians within the region. The use of ICS/LABA in these countries has been reported to range from 73.1% in the UAE to 83.7% in Qatar, with a similar proportion reported in Saudi Arabia (76.3%) and Kuwait (76.8%) [
5]. These estimates include instances in which ICS/LABA FDC is either used as the main asthma treatment or in combination with other therapies.
While the efficacy of different ICS/LABA FDCs has been established in traditional randomised controlled trials (RCTs) with strict eligibility criteria, their benefit in actual clinical practice may be reduced by numerous factors associated with asthma control [
15]. Many of these factors have been reported in the literature, such as adherence to treatment, comorbidities, polypharmacy and education [
16]. The extent to which locally relevant factors are accounted for in effectiveness studies of asthma therapeutic interventions is therefore important when determining the generalisability of evidence from these studies [
15]. Moreover, only around 3.3% of patients from actual clinical practice have been found to be eligible for inclusion in traditional RCTs [
17].
Studies conducted within the GCC countries are predominantly cross-sectional in nature and have been conducted in different healthcare settings. Most of these studies are descriptive and therefore only estimate the prevalence of asthma and, report factors associated with the disease [
10]. While the prevalence of asthma has been informed by the estimated ranges reported in these studies [
11], a synthesis of important asthma control factors in these countries will be informative for updates to local asthma management guidelines and practice. Systematic literature reviews (SLRs) are highest in the traditional hierarchy of evidence but few evidences of this type can be found in the region [
18‐
20]. This may be due to several reasons, including the quality and heterogeneity of studies, as well as perhaps the required time commitment of conducting such extensive reviews [
21]. Rapid reviews offer a time-sensitive alternative, using abridged SLR methods to generate evidence for healthcare decision makers. These reviews provide evidence summaries that can inform local treatment guidelines and other public health interventions [
22,
23]. Moreover, rapid reviews can provide useful evidence, specifically on pharmacological interventions [
24]. Such reviews have proven to be useful in certain healthcare settings as they can address gaps in knowledge through provision of reliable, user-friendly and timely evidence [
22,
23].
In the present study, a rapid literature review approach was used to address two conceptually sequential objectives: Review 1, to ascertain factors associated with asthma control in the GCC countries (Bahrain, Kuwait, Oman, Qatar, Saudi Arabia and the UAE); and Review 2, to assess the effectiveness of ICS/LABA FDC therapy in asthma control that are generalisable to asthma management in the GCC countries.
Discussion
We conducted this dual rapid review to provide timely evidence to inform asthma management guidelines and practice within the GCC countries. The local populations in the GCC countries share a common geographic area known as the Arab peninsular. While anthropology studies have suggested some genetic heterogeneity, there are common features among local populations within the GCC countries [
46]. An assessment of local asthma control factors was conducted and, how generalisable the evidence on ICS/LABA FDC effectiveness is, given that this therapeutic approach remains the most prevalent in the GCC countries. Our search identified studies from the GCC countries that reported association between asthma control and the factors contributing to it. These studies varied in their design; the majority of which were cross-sectional. Most studies identified were descriptive and were conducted in Saudi Arabia. This was anticipated given that Saudi Arabia has the largest landmass of the GCC countries [
47]. The disproportionate number of eligible publications on asthma control factors in the GCC countries up until 2018 (
n = 32) and after 2018 (
n = 19) may be due to several reasons. Notable among the reasons is the significant increase in medical institutions [
48] and academic research [
49] in the GCC countries within a relatively short period of time.
Our search strategy for the review on asthma control factors was developed to be as broad as possible. Our preliminary scoping search had revealed that many asthma related studies published in the region, particularly those reporting on prevalence, also reported on asthma control factors. Identified studies were generally lacking analytical framework to inform on the actual role of factors beyond association. For example, a number of factors reported in the literature may have been mediators or proxies of other putative factors not directly measured [
50]. This limited our ability to ascertain temporal components of asthma control and also, therefore, to sometimes distinguish between risk and prognostic factors [
51].
Of all the factors reported to be associated with asthma control within the GCC countries, asthma-related education recurred most often. These encompassed: education about asthma, asthma medicines and correct use of inhaler device; how to prevent and treat symptoms; and perceptions on the role of ICS and emergency room use for asthma care. While studies within GCC countries did not delineate between formal and informal approaches to asthma-related education, a systematic review of studies of educational interventions in asthma management found that delivery methods used in asthma education interventions were mostly informal [
52]. The review also reported that few of these asthma-related education interventions were home or community based. Education factors relating to patient knowledge about their symptoms, perceptions about their medications, and correct use of their device are all areas within the scope of the healthcare professional-patient relationship [
53]. Consequently, the lack of review and physician oversight is one of the contributors to poor asthma control and may lead to over-reliance on rescue medication. Studies from other parts of the world have shown that only around 50% of patients claim to be able to manage their asthma or have good knowledge about asthma treatment and adherence to controller medication [
54‐
56]. Hence, it may not be appropriate for patients to judge their own symptoms and take decisions on their therapies without guidance from an appropriately trained healthcare professional [
55].
For non-pharmacological interventions, our findings suggest that significant improvements to asthma management may help to better address asthma-related factors and therefore achieve optimal asthma control in the region. One such asthma management practice is the provision of asthma educators in all healthcare settings thereby filling the void due to time constraints of asthma treating physicians [
57].
Other factors associated with asthma control included demography, comorbidities, environmental factors, factors related to patient care, smoking, adherence, inhalant allergens and disease severity. As these clusters are likely to be interrelated, modifying the most distal in the interrelationships of these factors may alleviate asthma control due to their influence on multiple and more directly associated factors. Examples of distal factors in chronic diseases include education and socioeconomic factors [
58]. Further research is required to establish the interrelationships of these factors as this is important when developing public health interventions through multi-disciplinary approaches to asthma management.
Our review of ICS/LABA FDC effectiveness studies was insightful. Categorising ICS/LABA FDC studies as either efficacy or effectiveness studies is best considered as a spectrum. We explored this spectrum by using published criteria to provide an objective assessment of how well each of the studies could inform local clinical practice.
In the earlier published studies of ICS/LABA FDCs, lung function, symptoms, use of rescue medication and adverse events were most frequently reported. However, there were differences in the individual trials which meant that few comparisons could be made [
59]. This necessitated comparative studies in broad asthma patient populations within clinical practice. The first prospective, Phase III, pragmatic randomised controlled trial (RCT) conducted in conditions close to clinical practice, was reported in 2017 [
60]. Healthcare professionals and payers continue to be in need of such studies for treatments that have newly gained Marketing Authorisation (MA) [
61]. Given the few ICS/LABA FDC effectiveness RCTs identified, it was not surprising that none were from GCC countries. It was surprising, however, that our initial search output – which mostly comprised of traditional efficacy RCTs – included very few studies conducted in the GCC countries. The possible reasons for this are beyond the scope of our review. Nevertheless, this finding indicates that healthcare professionals and treatment guideline developers in the region will continue to rely on evidence presented in studies conducted elsewhere in order to make local evidence-based decisions on asthma management. As such, it is important to assess the generalisability of such evidence to local clinical practice and the appropriateness of its influence on local asthma management guidelines and practices of treating physicians within the GCC countries.
Despite identifying few (six) ICS/LABA FDC effectiveness studies, there was heterogeneity in how these studies met the applied criteria [
40‐
45]. A key consideration in effectiveness studies is ensuring that the study population is broad enough to be representative of the target patient population. Patient eligibility criteria in the studies ranged from controlled to partially controlled patients, as in the case of Usmani et al. [
40], to moderate-to-severe asthma in the case of Aubier et al. [
42]. The eligibility criteria adopted in Usmani et al. [
40] was therefore broader than that applied in Aubier et al. [
42]. Other studies defined patients simply by diagnosis of asthma. Woodcock et al. [
41] defined eligible patients as those with a general practitioner diagnosis, which was based on medical records. This was likely to be more reliable than the self-reported doctor diagnosis adopted by Beasley et al. [
43] and Hardy et al. [
44], and may explain some of the criticisms of the latter two studies [
62]. In the study of Beasley et al. [
43], as-needed budesonide-formoterol reduced the number of exacerbations compared to SABA alone, but the study was conducted in a population in which SABA alone was not indicated (GINA step II) [
4]. In the case of Hardy et al. [
44], their study of budesonide-formoterol reliever therapy compared to maintenance budesonide plus terbutaline may not have been conducted in patients with mild asthma only, as it was apparent that some moderate asthma patients were included based on the treatments taken.
With respect to study duration, Usmani et al. [
40] acknowledged that the 12-week follow-up period in each phase of their study of fluticasone propionate/formoterol vs fluticasone propionate/salmeterol was likely to have been insufficient to capture seasonal variations in asthma control and exacerbations. This is particularly important in the GCC countries given the effect of seasonality on asthma control. In contrast, Woodcock et al. [
41] showed that fluticasone furoate/vilanterol significantly improved asthma control compared with usual care, including ICS/LABA combinations, over a 52-week study. Aubier et al. [
42] (6 months observation period) and Hozawa et al. [
45] (8 weeks observation period) are therefore likely to have had insufficient patient observation period – though neither study discussed this.
There were significant differences in the sample sizes of the effectiveness RCTs of ICS/LABA combinations identified in the review. Usmani et al. [
40] acknowledged that one of the limitations of their study, in which they assessed change to and step-down from fluticasone propionate/formoterol, was the small sample of patients (
n = 225) studied. This meant study power was limited for detecting the predictors of response to step-down therapy. With a total of 8424 study patients, Aubier et al. [
42] calculated the sample size required for each group to detect a reduction in the proportion of patients experiencing a severe asthma exacerbation. The study by Woodcock et al. [
41], with 4233 patients, was reported to be the largest randomised, comparative effectiveness study conducted in a population intended to represent that seen in everyday clinical practice. This study was powered to detect relative improvements in asthma control. Both Beasley et al. [
43] and Hardy et al. [
44] conducted sample size calculations and studied 675 and 890 patients respectively.
Measurement of asthma control, which is the main goal of asthma management, also varied in the studies. Different tools were employed to assess asthma control. Usmani et al. [
40] suggested that inappropriate assessment of asthma control might contribute to overtreatment. As measured by the ACQ7, asthma control was similar between the fluticasone propionate/formoterol (1000/40 μg) and fluticasone propionate/salmeterol (1000/100 μg) groups; however, a significantly higher percentage of patients were controlled on fluticasone propionate/formoterol (1000/40 μg) when control was defined according to GINA [
42]. However, the view of the authors was that no standardised questionnaire exists for assessment of asthma control according to GINA. Aubier et al. [
42] reported no significant effect of the maintenance dose of budesonide/formoterol on the risk of exacerbation for patients with a post-bronchodilator peak expiratory flow value ≥80% predicted normal who comprised two-thirds of the population studied. The authors acknowledged that it was unexpected that a low peak expiratory flow value was the only variable predicting response to the higher maintenance dose of budesonide/formoterol. This could suggest that asthma outcomes other than time-to-first exacerbation are more relevant when assessing asthma patients in actual clinical practice. In Hozawa et al. [
45], the authors were of the view that FeNO represents airway inflammation. However, this outcome measure may be of very limited utility in the GCC countries.
Our dual rapid reviews had some limitations. We were unable to ascertain how comprehensive our two independent review searches were given the abridged SLR method utilised. Given our search strategy, it is probable that most of the published literature on asthma control factors in the GCC countries was identified. While our search on ICS/LABA FDC effectiveness was also comprehensive, it is possible that our initial assessment in determining effectiveness studies from the search output may have excluded certain publications of RCTs that their authors would consider to be closer to an effectiveness than efficacy study.
In our review approach we relied mostly on published and readily available information – we did not consult authors to enquire about any unpublished analysis addendum to their papers. Hence, any established relationship of the associated factors of asthma control may not have been considered in our review. The quality of some of the evidence considered, particularly for the review on asthma control factors in the GCC countries, varied considerably. The overall utility of studies on asthma control factors in our analysis was evaluated in view of the overall implication for practice and was also informed by the insights of our expert knowledge user.
Rapid reviews can provide data needed to address issues such as health system policies and effectiveness. The World Health Organisation and Cochrane have acknowledged the role of rapid reviews in building evidence-based policies and practices [
23]. A major strength of our review, which conforms to the World Health Organisation recommendations on rapid literature reviews, is that our research team included the end-user (a Consultant Pulmonologist representing those who would ultimately use the resulting evidence in clinical practice). Our clinical expert was consulted at all stages of the review process, providing input on review planning and initiation, conduct during the review, and assessment of results. This provides an important insight into the utility of our review. Moreover, the interdisciplinary team involved (including health outcomes scientist, epidemiologist, and pharmacist) enriched the review and its output.
Conclusion
Within the GCC countries, it is important that the effectiveness of ICS/LABA FDC is established in the context of local asthma control factors. This means that for evidence to be generalisable to the region, the studies from which evidence is generated must account for the asthma control factors pertinent in the region. This is achieved when studies are designed to minimise bias and adjust for putative factors associated with asthma control. Asthma-related education was the most recurrent cluster associated with asthma control in the GCC countries. Education factors that relate to patient knowledge about their symptoms, perceptions about their medications, and correct use of their device require physician oversight to ensure patients’ asthma control and, reduce over-reliance on rescue medication. These findings limit the local relevance of approaches that leave most asthma patients to judge their symptoms for taking medication. This finding is particularly important in the GCC countries where most patients studied have been reported to be on ICS/LABA FDCs.
Other factors identified as associated with asthma control in our study included demography, comorbidities, environmental factors, factors related to patient care, smoking, adherence, inhalant allergens and disease severity. These factors re-iterate the need for a multi-disciplinary approach to asthma management in the GCC countries.
Generalisability of evidence on the most administered therapeutic intervention in asthma management in the GCC countries requires that the studies are conducted in broad patient populations and in conditions close to actual clinical practice – as assessed by the effectiveness criteria utilised in our review. As our review of ICS/LABA FDC effectiveness studies highlights, the extent to which they can be considered generalisable to the GCC countries to influence treatment guidelines and clinical practice is variable.
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